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United States Patent | 5,118,665 |
Pickart | June 2, 1992 |
Compositions and methods for enhancing or restoring the resistance of a warm blooded animal to oxidative or inflammatory damage caused be release of reactive oxygen species by certain immune cells and other physiological processes are disclosed. The compositions include metal:peptide and metal:peptide:chelating agent complexes.
Inventors: | Pickart; Loren R. (Bellevue, County of King, WA) |
Assignee: | ProCyte Corporation (Redmond, WA) |
Appl. No.: | 478091 |
Filed: | February 9, 1990 |
Current U.S. Class: | 514/6; 514/8; 514/17; 514/18; 530/322; 530/329; 530/330; 530/331 |
Intern'l Class: | C07K 005/08; C07K 009/00 |
Field of Search: | 530/322,329,330,331 514/8,17,18,6 |
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Pickart et al., "Growth-Modulating Tripeptide (glycylhistidyllysine): Association with Copper and Iron in Plasma and Stimulation of Adhesive and Growth of Hepatoma Cells in Culture by Tripeptide-Metal Ion Complexes," J. Physiol. 102(2):129-139, 1980. Williams et al., "Glycyl-L-Histidyl-L-Lysine, a Growth Promoting Factor for Human Cells," Cytobios 27(105):19-25, 1980. Mochida Pharmaceutical Co., Ltd., "Anti-Inflammatory Injections Containing Superoxide Dismutase," Jpn. Kokai Tokkyo Koho, 81 07,720,27 Jan. 1981 (cited in Chem. Abstracts 94:145386f, 1981). Kwa, "Glycyl-L-Histidyl-L-Lysine: Synthesis of Analogs and NMR Studies," Ph.D. Thesis, University of Washington, 1983. Loker, "Synthesis of Blood Serum Peptide Cell Growth Factors," Ph.D. Thesis, University of Washington, 1980. Pickart, "The Biological Effects and Mechanism of Action of the Plasma Tripeptide Glycyl-L-Histidyl-L-Lysine," Lymphonkines 8:425-446, 1983. Poole et al., "Stimulation of Rat Peritoneal Mast Cell Migration by Tumor-Derived Peptides," Cancer Research 43:5857-5861, 1983. Raju et al., "Ceruloplasmin, Copper Ions, and Angiogenesis," JNCI 69(5):1183-1188, 1982. Freedman et al., "Structure of the Glycyl-L-Histidyl-L-Lysine-Copper(II) Complex in Solution," Biochemistry 21:4540-4544, 1982. Kwa et al., "PMR Studies of Cu(II) and Zn(II) Interaction with Glycyl-L-Histidyl-L-Lysine and Related Peptides," Peptides: Structure and Function 8:805-808, 1983. Perkins et al., "The Structure of a Copper Complex of the Growth Factor Glycyl-L-Histidyl-L-Lysine at 1.1 A Resolution," Inorganica Chimica Acta 82:93-99, 1984. Kimoto et al., "Enhancement of Antitumor Activity of Ascorbate Against Ehrich Ascites Tumor Cells by the Copper: Glycylglycylhistidine Complex," Cancer Research 43:824-828, 1983. Sorenson, "Copper Complexes: A Physiologic Approach to Treatment of Chronic Diseases," Comprehensive Therapy 11(4):49-64, 1985. Pickart et al., "Inhibition of the Growth of Cultured Cells and an Implanted Fibrosarcoma by Aroylhydrazone Analogs of the Gly-His-Lys-Cu(II) Complex," Biochem. Pharmacol. 32(24):3868-3871, 1983. Pickart et al., "Growth-Modulating Plasma Tripeptide May Function by Facilitating Copper Uptake Into Cells," Nature 288:715-717, 1980. "Newsreport on Use of GGH-Cu(II) and Ascorbic Acid," Natural Healing Annual 1986, p. 38 (M. Bricklin (ed.), Prevention Magazine, Rodale Press, Emmaus, Pa.). Pickart et al., "A Synthetic Tripeptide which Increases Survial of Normal Liver Cells, and Stimulates Growth in Hepatoma Cells," Biochem. Biophys. Res. Commun. 54(2):562-66, 1973. Aonuma et al., "Studies on Anti-Ulcerogenic Protein in Inflamed Rabbit Skin Tissues," Yakugaku Zasshi 104(4):362-73, 1984. Downey et al., "Acceleration of Wound Healing Using GHL-Cu(II)," Surgical Forum 36:573-75, 1985. Pickart et al., "A Human Plasma Growth Factor with Superoxide Dismutase-like and Wound-healing Properities," Superoxide Dim. Chem., Biol. Med. Proc. Int. Conf. 4th 1985 (Pub. 1986), 555-57. (cited in Chem Abstract 106:13579c). Frater-Schroder et al., "Tumor Necrosis Factor Type .alpha., a Potential Inhibitor of Endothelia Cell growth in vitro is Angiogenic in vivo," Proc. Natl. Acad. Sci. USA 34:5277-81 (1987). Pickart, "The use of Glycylhistidyllysine in Culture Systems," In Vitro 17(6):459-466 (1981). |
TABLE 1 ______________________________________ EFFECT OF HYDROPHYLIC MODIFICATIONS ON SOD MIMETIC ACTIVITY CONC. FOR RELATIVE 50% INHIB. to COMPOUND (umoles/ml) GHL-Cu ______________________________________ A GHL:Cu 0.059 100 GHL-Octyl Ester:Cu 0.007 810 B GHL:Cu 0.063 100 GHLVFV:Cu 0.023 229 C GHL:Cu 0.055 100 GHLAFA:Cu 0.010 561 GHL-Palmityl Ester:Cu 0.024 231 D GHL:Cu 0.006 100 LHG-Octyl Ester:Cu 0.010 60 LHGVFV:Cu 0.013 46 E GHL:Cu 0.031 100 GHL-Octyl Amide:Cu 0.017 182 ______________________________________ NOTES TO TABLE 1: GHL:Cu = glycylL-histidyl-L-lysine:copper(II) GHLOctyl Ester:Cu = glycylL-histidyl-L-lysine noctyl ester:copper(II) GHLVFV:Cu = glycylL-histidyl-L-lysyl-L-valyl-L-phenylalanyl-L-valine:copper(II) GHLAFA:Cu = glycylL-histidyl-L-lysyl-L-alanyl-L-phenylalanyl-L-alanine:copper(II) GHLPalmityl Ester:Cu = glycylL-histidyl-L-lysine npalmityl ester:copper(II) LHGOctyl Ester:Cu = lysylL-histidyl-L-glycine noctyl ester:copper(II) LHGVFV:Cu = lysylL-histidyl-glycyl-L-valyl-L-phenylalanyl-L-valine:copper(II) GHLOctyl Amide:Cu = glycylL-histidyl-L-lysine noctyl amide:copper(II)
TABLE 2 ______________________________________ EFFECT OF SEQUENCE AND AMINO ACID MODIFICATION ON SOD MIMETIC ACTIVITY CONC. FOR RELATIVE 50% INHIB. to COMPOUND (umoles/ml) GHL-Cu ______________________________________ A GHL:Cu 0.047 100 G(3-Benzyl)HL:Cu 0.033 145 G(3-Methyl)HL:Cu 0.008 616 B GHL:Cu 0.020 100 GHCadaverine:Cu 0.017 118 C GHL:Cu 0.059 100 G(3-Methyl)HLVFV:Cu 0.017 231 D GHL:Cu 0.006 100 GLH:Cu 0.020 75 LHG-Amide:Cu 0.070 21 E GHL:Cu 0.031 100 AHL:Cu 0.006 563 F GHL:Cu 0.033 100 GHCaprolactam:Cu 0.0008 4500 G GHL:Cu 0.067 100 HGL:Cu 0.0003 22300 ______________________________________ NOTES TO TABLE 2: GHL:Cu = glycylL-histidyl-L-lysine:copper(II) G(3Benzyl)HL:Cu = glycylL-(3-benzyl)-histidyl-L-lysine:copper(II) G(3Methyl)HL:Cu = glycylL-(3-methyl)-histidyl-L-lysine:copper(II) GHCadaverine:Cu = glycylL-histidyl-cadaverine:copper(II) G(3Methyl)HLVFV:Cu = alanylL-valine:copper(II) -L-lysyl-L-valyl-L-phenyl-- GLH:Cu = glycylL-lysyl-L-histidine:copper(II) LHGAmide:Cu = lysylL-histidyl-L-glycine amide:copper(II) AHL:Cu = alanylL-histidyl-L-lysine:copper(II) GHCaprolactam:Cu = lysylL-histidyl-caprolactam:copper(II) HGL:Cu = Lhistidyl-glycyl-L-lysine:copper(II)
TABLE 3 ______________________________________ EFFECT OF METAL ION ON SOD MIMETIC ACTIVITY CONC. FOR RELATIVE 50% INHIB. to COMPOUND RATIO (umoles/ml) GHL-Cu ______________________________________ A GHL:Cu 2:1 0.013 100 GHL:Mn 2:1 0.004 275 GHL-Octyl:Cu 2:1 0.011 100 GHL-Octyl:Mn 2:1 0.002 611 B GHL:Cu 2:1 0.040 100 GHL:Mn 2:1 0.001 4000 HGL:Mn 2:1 0.002 2000 GLH:Mn 2:1 0.006 2000 AHL:Mn 2:1 0.006 667 ______________________________________ NOTES TO TABLE 3. GHL:Cu = glycylL-histidyl-L-lysine:copper(II) GHL:Mn = glycylL-histidyl-L-lysine:manganese(II) GHLOctyl:Cu = glycylL-histidyl-L-lysine noctyl ester:copper(II) GHLOctyl:Mn = glycylL-histidyl-L-lysine noctyl ester:manganese(II) HGL:Mn = Lhistidyl-glycyl-L-lysine:manganese(II) GLH:Mn = glycylL-lysyl-L-histidine:manganese(II) AHL:Mn = alanylL-histidyl-L-lysine:manganese(II)
TABLE 4 ______________________________________ EFFECT OF ADDITIONAL CHELATION GROUPS ON SOD MIMETIC ACTIVITY CONC. FOR RELATIVE 50% INHIB. to COMPOUND RATIO (umoles/ml) GHL-Cu ______________________________________ A GHL:Cu 2:1 3.2 100 GHL:Cu:H 1:1:1 0.2 1600 GHL:Cu:Im 1:1:1 1.3 246 B GHLVFV:Cu 2:1 2.8 100 GHLVFV:Cu:H 1:1:1 0.2 1400 GHLVFV:Cu:Im 1:1:1 0.3 930 ______________________________________ NOTES TO TABLE 4. GHL:Cu = glycylL-histidyl-L-lysine:copper(II) GHL:Cu:H = glycylL-histidyl-L-lysine:copper(II):histidine GHL:Cu:Im = glycylL-histidyl-L-lysine:copper(II):imidazole GHLVFV:Cu = glycylL-histidyl-L-lysyl-L-valyl-L-phenylalanyl-L-valine:copper(II) GHLVFV:Cu:H = glycylL-histidyl-L-lysyl-L-valyl-L-phenylalanyl-L-valine:copper(II):histi ine GHLVFV:Cu:Im = glycylL-histidyl-L-lysyl-L-valyl-L-phenylalanyl-L-valine:copper(II):imida ole
TABLE 5 ______________________________________ EFFECT ON SOD MIMETIC ACTIVITY BY ALBUMIN BINDING MOIETIES CONC. FOR RELATIVE 50% INHIB. to COMPOUND RATIO (umoles/ml) GHL-Cu ______________________________________ A GHL:Cu 2:1 0.059 100 G(3-Methyl) 2:1 0.011 521 HLGW:Cu B GHL:Cu 2:1 0.047 100 GHLW:Cu 2:1 0.001 4700 ______________________________________ NOTES TO TABLE 5. GHL:Cu = glycylL-histidyl-L-lysine:copper(II) G(3Methyl)HLGW:Cu = glycylL-(3-methyl)-histidyl-L-lysyl-glycyl-L-tryptophan:copper(II) GHLW:Cu = glycylL-histidyl-L-lysyl-L-tryptophan:copper(II)
TABLE 6 ______________________________________ INHIBITION OF FERRITIN IRON RELEASE BY METAL:PEPTIDE COMPLEXES RATE PERCENT COMPOUND INC. A.sub.535 nm min INHIBITION ______________________________________ NONE 0.0060 0 GHL:Cu 0.0016 73% GHL Octyl Ester:Cu 0.0012 80% GHLVFV:Cu 0.0011 82% G(3-Methyl)HL:Cu 0.0010 83% HGL:Cu 0.0008 87% ______________________________________ NOTES TO TABLE 6: GHL:Cu = glycylL-histydyl-L-lysine:copper(II) GHL Octyl Ester:Cu = glycylL-histidyl-L-lysine noctyl ester:copper(II) GHLVFV:Cu = glycylL-histidyl-L-lysyl-L-valyl-L-phenylalanyl-L-valine:copper(II) G(3Methyl)HL:Cu = glycylL-(3-methyl)-histidyl-L-lysine:copper(II) HGL:Cu = Lhistidyl-glycyl-L-lysine:copper(II)
TABLE 7 ______________________________________ INHIBITION OF SUPEROXIDE AND FERRITIN DEPENDENT LIPID PEROXIDATION BY METAL:PEPTIDE COMPLEXES RATE nmole PERCENT COMPOUND MDA/min/ml INHIBITION ______________________________________ A NONE 0.220 0 GHL:Cu 0.084 62% GHL Octyl Ester:Cu 0.060 73% GHLVFV:Cu 0.140 36% B NONE 0.150 0 G(3-Methyl)HL:Cu 0.104 31% HGL:Cu 0.020 87% ______________________________________ NOTES TO TABLE 7: GHL:Cu = glycylL-histidyl-L-lysine:copper(II) GHL Octyl Ester:Cu = glycylL-histidyl-L-lysine noctyl ester:copper(II) GHLVFV:Cu = glycylL-histidyl-L-lysyl-L-valyl-L-phenylalanyl-L-valine:copper(II) G(3Methyl)HL:Cu = glycylL-(3-methyl)-histidyl-L-lysine:copper(II) HGL:Cu = Lhistidyl-glycyl-L-lysine:copper(II)